TY - JOUR
T1 - Functional human IgA targets a conserved site on malaria sporozoites
AU - Tan, Joshua
AU - Cho, Hyeseon
AU - Pholcharee, Tossapol
AU - Pereira, Lais S.
AU - Doumbo, Safiatou
AU - Doumtabe, Didier
AU - Flynn, Barbara J.
AU - Schön, Arne
AU - Kanatani, Sachie
AU - Aylor, Samantha O.
AU - Oyen, David
AU - Vistein, Rachel
AU - Wang, Lawrence
AU - Dillon, Marlon
AU - Skinner, Jeff
AU - Peterson, Mary
AU - Li, Shanping
AU - Idris, Azza H.
AU - Molina-Cruz, Alvaro
AU - Zhao, Ming
AU - Olano, Lisa Renee
AU - Lee, Patricia J.
AU - Roth, Alison
AU - Sinnis, Photini
AU - Barillas-Mury, Carolina
AU - Kayentao, Kassoum
AU - Ongoiba, Aissata
AU - Francica, Joseph R.
AU - Traore, Boubacar
AU - Wilson, Ian A.
AU - Seder, Robert A.
AU - Crompton, Peter D.
N1 - Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
PY - 2021/6/23
Y1 - 2021/6/23
N2 - Immunoglobulin (Ig)A antibodies play a critical role in protection against mucosal pathogens. However, the role of serum IgA in immunity to nonmucosal pathogens, such as Plasmodium falciparum, is poorly characterized, despite being the second most abundant isotype in blood after IgG. Here, we investigated the circulating IgA response in humans to P. falciparum sporozoites that are injected into the skin by mosquitoes and migrate to the liver via the bloodstream to initiate malaria infection. We found that circulating IgA was induced in three independent sporozoite-exposed cohorts: individuals living in an endemic region in Mali, malaria-naïve individuals immunized intravenously with three large doses of irradiated sporozoites, and malaria-naïve individuals exposed to a single controlled mosquito bite infection. Mechanistically, we found evidence in an animal model that IgA responses were induced by sporozoites at dermal inoculation sites. From malaria-resistant individuals, we isolated several IgA monoclonal antibodies that reduced liver parasite burden in mice. One antibody, MAD2-6, bound to a conserved epitope in the amino terminus of the P. falciparum circumsporozoite protein, the dominant protein on the sporozoite surface. Crystal structures of this antibody revealed a unique mode of binding whereby two Fabs simultaneously bound either side of the target peptide. This study reveals a role for circulating IgA in malaria and identifies the amino terminus of the circumsporozoite protein as a target of functional antibodies.
AB - Immunoglobulin (Ig)A antibodies play a critical role in protection against mucosal pathogens. However, the role of serum IgA in immunity to nonmucosal pathogens, such as Plasmodium falciparum, is poorly characterized, despite being the second most abundant isotype in blood after IgG. Here, we investigated the circulating IgA response in humans to P. falciparum sporozoites that are injected into the skin by mosquitoes and migrate to the liver via the bloodstream to initiate malaria infection. We found that circulating IgA was induced in three independent sporozoite-exposed cohorts: individuals living in an endemic region in Mali, malaria-naïve individuals immunized intravenously with three large doses of irradiated sporozoites, and malaria-naïve individuals exposed to a single controlled mosquito bite infection. Mechanistically, we found evidence in an animal model that IgA responses were induced by sporozoites at dermal inoculation sites. From malaria-resistant individuals, we isolated several IgA monoclonal antibodies that reduced liver parasite burden in mice. One antibody, MAD2-6, bound to a conserved epitope in the amino terminus of the P. falciparum circumsporozoite protein, the dominant protein on the sporozoite surface. Crystal structures of this antibody revealed a unique mode of binding whereby two Fabs simultaneously bound either side of the target peptide. This study reveals a role for circulating IgA in malaria and identifies the amino terminus of the circumsporozoite protein as a target of functional antibodies.
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U2 - 10.1126/scitranslmed.abg2344
DO - 10.1126/scitranslmed.abg2344
M3 - Article
C2 - 34162751
AN - SCOPUS:85108997828
VL - 13
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 599
M1 - eabg2344
ER -